Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology characterized the production of autoantibodies against self tissues. SLE is primarily a disease of women, and is a clinically heterogeneous disorder with involvement of multiple organ systems. Epidemiological and family studies have shown convincingly that SLE clusters in families, suggesting a genetic basis for the disease. The relative risk of developing SLE in a family with one lupus proband is approximately 10-fold higher than control families. The underlying hypothesis of this proposal, based on a large body of evidence, is that SLE is a polygenic disease, with the inheritance of a few genes of major effect contributing to susceptibility. The overall objective of this application is to identify the susceptibility loci for SLE within the human genome. The proposed study will utilize gene mapping with highly informative short tandem repeat polymorphism (STRPs) in sibling pairs of women with SLE. The design of the study is as follows: 1) A registry of approximately 300 sib pairs of female SLE patients and their available parents will be established. 2) A comprehensive data base of family history and clinical/serologic information will be established for each patient. 3) A Lupus Sib Pair Biological Resource of serum, DNA, immortalized cell lines, and Class II MHC genotypes will be developed. 4) Each sib pair and available parents will be genotyped using approximately 200 STRP markers in a genome screen at 15 to 20 centiMorgan (cM) intervals. 5) Statistical genetic analysis of the collected marker data will be used to detect regions of the genome which contribute susceptibility to SLE using the sib pair methods. Once linkage analysis has identified suspicious areas of the genome, additional markers will be tested to narrow the region(s) of interest to a 1-2 cM interval. Candidate genes in the region will then be investigated and/or overlapping YAC contigs will e developed. The use of the affected sib pair approach to gene mapping in SLE offers a number of advantages which include being model (mode of inheritance) independent, having sufficient numbers for statistical significance, and providing enough genetic contribution to minimize problems of heterogeneity. The eventual identification of the genes that are genetically linked to SLE will provide a framework for understanding the etiology of this disease and subsequently developing effective intervention strategies.
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